ABSTRACT The main objective of the proposed research is to examine, for the first time, intergenerational transmission of human brain networks using a natural cross-fostering design. We take reading-related brain networks, in particular those related to phonological and orthographic processing (as well as in language- and more preliminarily in math-related processes), as model systems because of the potentially differential impact of genetic and environmental factors on these networks and corresponding behavioral phenotypes. In addition, impairment of these neurocognitive processes is associated with specific learning disorder of word reading (aka decoding-based reading disorder [RD] or developmental dyslexia) that has a lifetime prevalence of 5- 10%, and an increased risk of the offspring developing RD by 4 to 8 times the general population with an immediate family member with RD. The proposed natural cross-fostering design addresses a critical question about the mechanisms of intergenerational effects, i.e., whether they are genetic (G), prenatal (PreE) or postnatal environmental (PostE) in origin. This is only now possible with the widespread availability of in-vitro fertilization (IVF). We will obtain cognitive measures, and functional and structural MRI, in healthy families (triads) at a pace of 30 families per site per year. We will examine parent-offspring correlations, including brain- brain correlations, across four groups of IVF children that receive distinctive G/PreE/PostE contributions from their rearing parents as well as a fifth group of naturally conceived children (N=60 triads per group, with children of ages 8-11, half with daughters and the other half with sons): (1) the HOMOLOGOUS group in which offspring conceived through IVF are borne and reared by their genetic parents, thus being exposed to maternal and paternal G/PreE/PostE influences; (2) the DONOR EGG and (3) DONOR SPERM groups, in which offspring are conceived from donor eggs/sperm, and hence rearing mothers/fathers only have PreE/PostE, not G, influence on their offspring; (4) the gestational SURROGACY group in which offspring are borne through non-genetic, non-rearing mothers, and hence rearing parents only have G/PostE but no PreE influences over their offspring; and (5) the NATURAL conception group in which naturally conceived offspring are borne and reared by their genetic parents, thus being exposed to maternal and paternal G/PreE/PostE influences and without the influence of IVF. Fathers? PreE influence is typically considered minimal. The specific aims of the proposal are: to examine parent-offspring (dyad) correlations, to examine the extent to which environmental and genetic factors contribute to shared variance in reading- and language-related cognitive and neurobiological processes, to examine parent-of-origin effects, and to dissociate G, PreE and PostE influences. A successful outcome will establish a new paradigm for studying genetic and environmental influences on brain networks, and ultimately provide us with important information about risk/protective factors, windows of opportunity to intervene, and development of early intervention and preventive strategies of RD.